Final checkup of neoplastic DNA replication: evidence for failure in decision-making at the mitotic cell cycle checkpoint G(1)/S.
OBJECTIVE
Processing of epigenomic transcriptional information by cell cycle phase G(1) and decision-making at checkpoint G(1)/S are the final organizational steps preceding gene replication in transcriptional reorientation programs (i.e., switches from proliferation to cycle arrest and neoplastic transformation). Further analyses of cycle progression will open up new approaches in antineoplastic therapy.


METHODS
The following bibliographic databases were consulted: Central Medical Library Cologne, PubMed (English), the last search was done on April 23,2008 and key words searched were: cell cycle, cell memory, DNA methylation, embryonal/neoplastic stem cells, enzyme-modulated chromatin, G(1)-G(1)/S checkpoint, genomic/epigenomics, genomic viral DNA, histones, telomere/telomerases, transcription factors, neoplastic transformation, senescence.


RESULTS
Gene transcription and epigenomic surveillance form a functional entity. In proliferation programs, transcriptional information is mediated by chromatin and DNA methylation, analyzed and processed in G(1) phase, and converged on the parental checkpoint G(1)/S for final decision-making on DNA replication. Genomic reorientation appears to be associated with transcriptional instability, which normally is corrected, possibly during the G(2)/M phase, to new levels of epigenomic equilibria. We speculate that daughter stem cells inherit persistent neoplasm-specific transcriptional instabilities through failure of the parental G(1)/S checkpoint. Foreign, silenced, potentially oncogenic DNA sequences, i.e. regular components of the human genome such as endogenous retroviruses, could conceivably be activated for expression in neoplastic transformation by epigenomic histone deacetylase/acetyl transferase/histone methyltransferase-mixed lineage leukemia deregulations.


CONCLUSIONS
Failure of cell cycle G(1)/S decision-making for DNA replication is the final and possibly a major cause in neoplastic transformation. Therefore, further analysis of the dynamics of G(1)-G(1)/Sphases could provide new opportunities for therapeutic strategies.
Prindull
Gregor
G
Department of Pediatrics, University of Göttingen, Göttingen, Germany. GregorPrindull@aol.com
D000818:Animals; D002471:Cell Transformation, Neoplastic; D018899:CpG Islands; D019175:DNA Methylation; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000235:genetics*; D053595:Embryonic Stem Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D016193:G1 Phase; D042822:Genomic Instability; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism; D016196:S Phase; D016615:Telomere; D014158:Transcription, Genetic
D004273:DNA, Neoplasm